1-methoxy-2-phenyl ethenes useful for the preparation of 5-carboxaldehyde-2-3-dihydrobenzoxepines

ABSTRACT

The present invention relates to the compounds of general formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein R, R 1 , R 2  are as defined in claim  1.    
           
         
       
    
     Compounds of formula (I) are particularly useful for preparing 3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepines derivatives.

FIELD OF THE INVENTION

The present invention relates to 1-methoxy-2-phenyl-ethene derivativesand their use for the preparation of3,3-dimethyl-5-formyl-2,3-dihydro-benzoxepines derivatives.

BACKGROUND OF THE INVENTION

3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepine derivatives (formula II):

are disclosed in EP 1140893 B1 and U.S. Pat. No. 6,596,758 patents asintermediates for the preparation of 5-(3,3-dimethyl-2,3-dihydrobenzoxepin-5-yl)-2,4-pentadienoic acid derivatives useful for treatingdyslipidemias, athero-sclerosis and diabetes.

In these patents, compounds of formula II are prepared according to thefollowing scheme:

This synthetic method involves four chemical steps starting frombenzoxepinone and the yields, as reported, are moderate.

Furthermore, this synthetic pathway cannot be easily scaled up tocommercial implementation.

It now has been found a novel improved synthetic route for preparing thecompounds of formula (II) which is unexpectedly applicable at industrialscale.

Advantageously, the compounds of formula (II) can be obtained in onlythree steps, each being characterized by high yields.

As another advantage, the invention provides an economical and efficientroute for preparing the compounds of formula (II).

According to the present invention, compounds of formula (II) areprepared from new compounds of formula (I):

Thus, in one aspect, the present invention is related to compounds ofgeneral formula (I):

Each of R is independently chosen from a halogen atom; a cyano group; anitro group; a carboxy group; an optionally halogenated(C₁-C₁₈)alkoxycarbonyl group; an R_(a)—CO—NH— or R_(a)R_(b)N—CO— group[in which R_(a) and R_(b) independently represent optionally halogenated(C₁-C₁₈)alkyl; a hydrogen atom; (C₆-C₁₀)aryl or (C₆-C₁₀)aryl(C₁-C₅)alkyl(where the aryl parts are optionally substituted by a halogen atom, byan optionally halogenated (C₁-C₅)alkyl group or by an optionallyhalogenated (C₁-C₅)alkoxy group); (C₃-C₁₂)cycloalkyl optionallysubstituted by a halogen atom, by an optionally halogenated (C₁-C₅)alkylgroup or by an optionally halogenated (C₁-C₅)alkoxy group]; anoptionally halogenated (C₁-C₁₈)alkyl group; optionally halogenated(C₁-C₁₈)alkoxy; and (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₅)alkyl,(C₆-C₁₀)aryloxy, (C₃-C₁₂)cyclo-alkyl, (C₃-C₁₂)cycloalkenyl,(C₃-C₁₂)cycloalkyloxy, (C₃-C₁₂)cycloalkenyloxy; (C₆-C₁₀)aryloxycarbonylor (C₆-C₁₀)arylcarbonyl; in which the aryl, cycloalkyl and cycloalkenylparts are optionally substituted by a halogen atom, by an optionallyhalogenated (C₁-C₅)alkyl or by an optionally halogenated (C₁-C₅)alkoxy;

p represents 0, 1, 2, 3 or 4;

R₁ and R₂ are a (C₁-C₁₈)alkyl group or form together —(CH₂)_(n)— whereinn represents 2, 3 or 4.

The formula (I) encompasses all types of geometric isomers andstereoisomers of the compounds of formula (I).

As used above and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched, having 1 to 18 carbon atoms in the chain. Preferred alkylgroups have 1 to 12 carbon atoms in the chain.

“Branched alkyl” means that one or more lower alkyl groups such asmethyl, ethyl or propyl are attached to a linear alkyl chain.

“Lower alkyl” means an alkyl group with 1 to about 4 carbon atoms in thechain which may be straight or branched.

Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl or octadecyl.

The alkyl group may be substituted by one or more halogen atomsrepresenting thus an “halogenoalkyl” group.

“Halogen atoms” means fluorine, chlorine, bromine or iodine atoms.Preferred are fluorine, chlorine or bromine atoms and more preferred isfluorine atoms.

The “halogenoalkyl” groups may thus refer to “perfluoroalkyl”, whichmeans groups corresponding to the formula “—C_(n)F_(2n+1)” wherein nrepresents 1 to 18.

Examples of perfluoroalkyl groups are pentafluoroethyl ortrifluoro-methyl.

“Alkoxy” means an alkyl-O— group wherein the alkyl group is as hereindescribed. Exemplary alkoxy groups include methoxy, ethoxy,isopropyloxy, butoxy and hexyloxy radicals.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system ofabout 3 to 12 carbon atoms. Preferred ring sizes of the ring systeminclude about 3 to 8 and more preferably 5 to 6 ring atoms. Thecycloalkyl is optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. Exemplary monocyclic cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, cyclododecyl and the like.

Exemplary multicyclic cycloalkyl include 1-decalyn, norbornyl and thelike.

“Cycloalkenyl” means a non-aromatic mono- or multicyclic ring system ofabout 3 to about 12 carbon atoms, preferably of about 5 to about 10carbon atoms, and which contain at least one carbon-carbon double bond.

Preferred ring size of rings of the ring system include about 5 to about6 ring atoms. The cycloalkenyl is optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein. Exemplary monocyclic cycloalkenyl includecyclopentenyl, cyclohexenyl, cycloheptenyl and the like. An exemplarymulticyclic cycloalkenyl is norbornylenyl.

“Aryl” means an aromatic monocyclic or multicyclic ring system of about6 to about 10 carbon atoms. The aryl is optionally substituted with oneor more “ring system substituents” which may be the same or differentand are as defined herein. Exemplary aryl groups include phenyl ornaphtyl, or substituted phenyl or substituted naphtyl.

“Alkenyl” means an aliphatic hydrocarbon group containing one or morecarbon-carbon double bond and which may be straight or branched, havingabout 2 to about 12 carbon atoms in the chain, and more preferably about2 to about 4 carbon atoms in the chain.

“Branched alkenyl” means that one or more lower alkyl or alkenyl groupssuch as methyl, ethyl or propyl are attached to a linear alkenyl chain.“Lower alkenyl” means about 2 to about 4 carbon atoms in the chain,which may be straight or branched. The alkenyl group may be substitutedby one or more halogen atoms. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl,heptenyl, octenyl, cyclohexyl-butenyl and decenyl.

“Aryloxy” means an aryl-O— group wherein the aryl group is as definedherein. Exemplary groups include phenoxy and 2-naphtyloxy.

“Aryloxycarbonyl” means an aryl-O—CO— group wherein the aryl group is asdefined herein. Exemplary aryloxycarbonyl groups includephenoxy-carbonyl and naphtoxycarbonyl.

“Arylcarbonyl” refers to an aryl-CO— group wherein the aryl group is asdefined herein.

Exemplary arylcarbonyl group includes benzoyl.

The (C₆-C₁₀) aryl, (C₃-C₁₂) cycloalkyl, (C₃-C₁₂) cycloalkenyl areoptionally substituted by one or more “ring system substituents”.

“Ring system substituents” mean substituents attached to aromatic ornon-aromatic ring systems, inclusive of halogen atoms, an optionallyhalogenated (C₁-C₅) alkyl, or an optionally halogenated (C₁-C₅)alkoxy,halogen, alkyl and alkoxy being as defined herein,

The wording “in which the aryl, cycloalkyl and cycloalkenyl parts areoptionally substituted by a halogen atom, by an optionally halogenated(C₁-C₅)alkyl or by an optionally halogenated (C₁-C₅)alkoxy” means thatthe aryl, cycloalkyl, cycloalkenyl groups are optionally substituted byone or more substituents selected from the group consisting of:

-   -   halogen atoms;    -   alkyl groups optionally substituted by one or more halogen        atoms, and    -   alkoxy groups optionally substituted by one or more halogen        atoms.

The wording “optionally halogenated” means, in the context of thedescription, optionally substituted by one or more halogen atoms.

Preferably, each of R independently represents a halogen atom, anoptionally substituted halogenated (C₆-C₁₀) arylcarbonyl, an optionallyhalogenated (C₁-C₁₈) alkyl, an optionally halogenated (C₁-C₁₈) alkoxy,or an optionally halogenated (C₆-C₁₀) aryl.

More preferably, R represents a (C₁-C₁₈) alkoxy group, more preferably a(C₁-C₄) alkoxy group and, most preferably, a methoxy group.

Preferably, p is 1 or 2 and more preferably 1.

R may be located in ortho (6), meta (3 or 5) and para (4) position onthe phenyl ring with regard to the methoxy ethenyl group, preferably inmeta position, more preferably at position 5.

Preferably, R₁ and R₂ represent independently a (C₁-C₄) alkyl group, andmore preferably methyl, ethyl or isopropyl.

In another preferred embodiment, R₁ and R₂ form together a —(CH₂)_(n)—chain in which n represents 2 or 3.

According to the invention, a preferred embodiment is the compound offormula (I) in which R1 and R2 both represent a C₂H₅— group or formtogether a —CH₂—CH₂— group.

Preferred compounds of formula (I) can be selected from the groupconsisting in:

-   1)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-bromo-phenyl)-ethene-   2)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-3-methoxy-phenyl)-ethene-   3)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-4,5-dichloro-phenyl)-ethene-   4)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-fluoro-phenyl)-ethene-   5)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-(para-chlorobenzoyl)-phenyl)-ethene-   6)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-trifluoro-methyl-phenyl)-ethene-   7)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-fluoro-2-phenyl)-ethene-   8)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-chloro-phenyl)-ethene-   9)    E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-4,5-dimethoxy-phenyl)-ethene-   10)E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-phenyl-phenyl)-ethene-   11)E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy)-phenyl)-ethene-   12)E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-methoxy-phenyl)-ethene.-   13)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-bromo-phenyl)-ethene-   14)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-3-methoxy-phenyl)-ethene-   15)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-4,5-dichloro-phenyl)-ethene-   16)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-fluoro-phenyl)-ethene-   17)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-(para-chlorobenzoyl)-phenyl)-ethene-   18)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-trifluoro-methyl-phenyl)-ethene-   19)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-fluoro-2-phenyl)-ethene-   20)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-chloro-phenyl)-ethene-   21)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-4,5-dimethoxy-phenyl)-ethene-   22)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-phenyl-phenyl)-ethene-   23)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy)-phenyl)-ethene-   24)E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-methoxy-phenyl)-ethene.

According to a particularly advantageous embodiment of the invention, apreferred compounds is a compound in which R=5-OCH₃,p=1 and R1 and R2both form a —CH₂—CH₂— group (formula (IA)).

According to a particularly advantageous embodiment of the invention, apreferred compound is in which R=7-OCH₃, p=1 and R1=R2=C₂H₅— (formula(IB)).

Method for Preparing Compounds of Formula (II) Starting from Compoundsof Formula (I)

According to the invention, the compounds of formula (I) are used forthe preparation of compounds of formula (II) according to scheme 2:

Thus, in another aspect, the present invention is directed to a methodfor preparing compounds of formula (II), comprising:

a) reacting the compound of formula (I) with an acid; and optionally

b) isolating the obtained compound of formula (II).

The conversion of the compound of formula (I) into the compound offormula (II) is carried out in the presence of an acid. The acid acts asa catalyzing agent. There is no particular restriction on the nature ofthe acid used in this reaction and any acid conventionally used in areaction of this type may equally be used here, provided that it has noadverse effect on other parts of the molecule.

Suitable acids for catalyzing the cyclization reaction in step i)include inorganic acids such as chlorhydric acid, sulfuric acid, nitricacid and phosphoric acid; sulfonic acids such as methanesulfonic acid,ethane-sulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

Inorganic acids are most preferred, and notably sulfuric acid.

The amount of acid is for example 0.2 to 2 moles and more preferably 0.5to 1 moles relative to 1 mole of compound (I).

There is no particular restriction on the nature of the solvent to beemployed, provided that it has no adverse effect on the reaction or onthe reagent involved.

Suitable solvents for step a) are polar and aprotic solvents such asacetonitrile, N-methylpyrrolidone, N,N-dimethylformamide (DMF) anddimethylsulfoxide (DMSO), DMF being particularly preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, it has been found convenient to carry out the reaction at atemperature from about room temperature to about 100° C. and preferablyfrom about 50° C. to 100° C.

The time required for the reaction may also vary widely, depending onmany factors, notably the reaction temperature and the nature of thereagents. However, provided that the reaction is effected under thepreferred conditions outlined above, a period from about 3 hours toabout 20 hours will usually be sufficient.

The compounds thus prepared may be recovered from the reaction mixtureby conventional means, for example the compounds may be recovered bydistilling of the solvent from the reaction mixture or, if necessary,after distilling of the solvent from the reaction mixture, pouring theresidue into water, followed by extraction with a water-immiscibleorganic solvent and distilling of the solvent from the extract.Additionally, the product can, if desired, be further purified byvarious well known techniques, such as recrystallization,reprecipitation or the various chromatography techniques, notably columnchromatography or preparative thin layer chromatography.

Preferred compounds of formula (II) which may conveniently be preparedstaring from corresponding compounds of formula (I) according to thepresent invention can be chosen from the group consisting in:

3,3-dimethyl-5-formyl-7-bromo-2,3-dihydrobenzoxepine,

3,3-dimethyl-5-formyl-9-methoxy-2,3-dihydrobenzoxepine,

3,3-dimethyl-5-formyl-7,8-dichloro-2,3-dihydrobenzoxepine,

3,3-dimethyl-5-formyl-7-fluoro-8-chloro-2,3-di-hydrobenzoxepine,

3,3-dimethyl-5-formyl-7-(para-chlorobenzoyl)-2,3-dihydrobenzoxepine,

3,3-dimethyl-5-formyl-7-trifluoromethyl-2,3-di-hydrobenzoxepine,

3,3-dimethyl-5-formyl-7-fluoro-2,3-dihydrobenzoxepine,

3,3-dimethyl-5-formyl-7-chloro-2,3-dihydrobenzoxepine,

3,3-dimethyl-5-formyl-7,8-dimethoxy-2,3-dihydro-benzoxepine,

3,3-dimethyl-5-formyl-7-phenyl-2,3-dihydrobenzoxepine,

3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepine,

3,3-dimethyl-5-formyl-7-methoxy-2,3-dihydrobenzoxepine.

Method for Preparing the Compounds of Formula (I)

The compounds useful according to the invention may be prepared by theapplication or adaptation of known methods, by which are meant methodsused heretofore or described in the literature, for example thosedescribed by R. C. Larock in Comprehensive Organic Transformations, VCHPublishers, 1989.

In another aspect, the invention relates to a method for preparing thecompound of formula (I) comprising:

-   -   ii) reacting an aldehyde (V) resulting from step i) with a        phosphorus ylid prepared from the reaction of a phosphonate        (XIIa) or phosphonium salt (XIIb) with a base,

-   -   T₁ and T₂ represent independently (C₁-C₅) alkyl, T₃, T₄, T₅        represent independently (C₁-C₅) alkyl or (C₆-C₁₀) aryl, and        optionally    -   iii) isolating the obtained compound of formula (I).

Preferably, the aldehyde (V) is prepared by:

-   -   i) reacting a compound of formula (III) with a compound of        formula (IV) in the presence of a base

-   -   wherein R, R₁, R₂ and p are as defined hereabove, X represents        an halogen atom, a (C₆-C₁₀) arylsulfonyloxy, a (C₁-C₆)        alkylsulfonyloxy.

“Arylsulfonyloxy” means an aryl-SO₂— group wherein the group aryl is asdefined herein. Examples of arylsulfonyloxy groups include the tosylgroup of formula p-CH₃(C₆H₅)—SO₃—.

“Alkylsulfonyloxy” means an alkyl-SO₂— group wherein the group alkyl isas defined herein. Examples of alkylsulfonyloxy group include the mesylgroup of formula CH₃—SO₃—.

This synthetic route is illustrated in scheme 3:

Step i)

The reaction of step i) is carried out in the presence of a base. Thereis no particular restriction on the nature of the base to be used inthis reaction, and any base conventionally used in reactions of thistype may equally be used here, provided that it has no adverse effect onother parts of the molecule.

Examples of suitable basis include alkali metal hydrides such as sodiumhydride and potassium hydride; (C₁-C₁₀) alkyllithium compounds such asmethyllithium and butyllithium, and alkali metal alkoxides, such assodium methoxide and sodium ethoxide, and alkali metal carbonates, suchas potassium carbonate and sodium carbonate. Of these, the alkali metalcarbonates are particularly preferred.

The amount of base is for example 2 to 10 moles and preferably 2 to 3moles relative to 1 mole of compound III.

There is no particular restriction on the nature of the solvent to beused, provided that is has no adverse effect on the reaction or on thereagent involved.

Examples of suitable solvents include hydrocarbons, which may bearomatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane,cyclohexane, benzene, toluene and xylene; aprotic polar solvents such asN,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide. Of these,toluene, N-methylpyrrolidone, dimethylformamide and dimethylsulfoxideare particularly preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, it has been found convenient to carry out the reaction at atemperature of from about room temperature (20° C.) to 150° C., and morepreferably of from 50° C. to 100° C.

The molar ratio of compound (IV) relative to compound (III) may varyfrom 1.0 to 1.5 equivalent, preferably from 1.05 to 1.1.

Step ii)

The reaction implemented in stage ii) is either a Wittig reaction or aHorner-Emmons/Wadsworth-Emmons reaction. These reactions are bothwell-known in the art and typically involve the preparation of areactive ylid. For any further information on that subject, referencemay be made to G. Wittig, U. Schöllkopf, Ber. 87, 1318 (1954); G.Wittig, W. Haag, ibid. 88, 1654 (1955); L. Horner et al., Ber. 91, 61(1958); idem et al., ibid. 92, 2499 (1959); W. S. Wadsworth, Jr., W. D.Emmons, J. Am. Chem. Soc. 83, 1733 (1961).

When the ylid is prepared from a phosphonium salt (compound XIIb), thereaction implemented is a Wittig reaction.

When the ylid is prepared from a phosphonate (compound XIIa), thereaction is called a Horner-Emmons or Wadsworth-Emmons reaction.

At stage ii), the ylid is prepared by reacting a base either with acompound (XIIa) or with a compound (XIIb). The base used has to besufficiently strong to remove an hydrogen atom in the alpha-position ofthe phosphorus.

Typically, the base is selected from the group consisting of alkalimetal hydrides, alkali metal carbonates, alkali metal amides, (C₁-C₁₀)alkyllithium, and alkali metal alkoxides.

In the context of the invention, alkali metal hydrides such as sodiumhydride and potassium hydride, and alkali metal alkoxides such as sodiummethoxide, sodium ethoxide and potassium tert-butoxide are particularlypreferred.

The reaction of the base on the compounds (XIIa) or (XIIb) is effectedin a solution, preferably in an aprotic solvent, and notably in asolvent able to dissolve the phosphonate (XIIa) and respectively thephosphonium salt (XIIb).

Examples of suitable solvents are notably aprotic solvents, such asaromatic hydrocarbons, as for example benzene and toluene, ethers, suchas diethylether, dioxane or tetrahydrofuran; aprotic polar solvents suchas N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or HMPTand mixtures thereof.

The reaction of step ii) can take place over a wide range oftemperatures, depending on the acidity of the compound (XIIa),respectively (XIIb), which means the ability to remove the hydrogen atomon the alpha-position with regard to the phosphorus. The type of thebase used directly influences the choice of the reaction temperature.Thus, the stronger the base is, the lower the reaction temperature is.

When the base is an alkali metal alkoxide, a temperature comprisedbetween −10° and 100° C. is generally suitable.

A stoichometric amount of basis is generally required in step ii) toconvert the phosphonate or the phosphonium salt into the correspondingylid. However, a slight excess of base may be used to ensure the totalconversion of the compounds (XIIa) or (XIIb) into the ylid. Thus, themolar ratio of the base relative to the compound (XIIa), respectively(XIIb), is maintained between 1 and 1.2, preferably between 1 and 1.1,and more preferably between 1 and 1.05. The concentration of thecompound (XIIa), respectively (XIIb), in the reaction mixture is notcritical according to the invention. The concentration may vary between0.01 mol/L and 10 mol/L, preferably between 0.1 and 1 mol/L.

According to a preferred embodiment, the ylid resulting from thereaction of the compound (XIIa), respectively (XIIb), with a base isperformed before adding the aldehyde (V).

Preferably, the phosphorus ylid is prepared from a phosphonium salt(XIIb), more preferably from CH₃OCH₂PPh₃Cl.

According to a preferred embodiment, the ylid is prepared by reactingCH₃OCH₂PPh₃Cl with potassium tert-butoxide in tetrahydrofuran.

Compounds of Formula (IV)

In another aspect, the invention relates to compounds of formula (IV):

wherein X represents an halogen atom, a (C₁-C₆) alkylsulfonyloxy or a(C₆-C₁₀) arylsulfonyloxy,R₁, R₂ are a (C₁-C₁₈) alkyl group or form together a —(CH₂)_(n)—,wherein n represents 2, 3 or 4,with the exclusion of the compounds of formula (IV), wherein X═I andR₁═R₂═CH₃; X═I, Br or pCH₃—(C₆H₅)SO₃—, and R₁ and R₂ form together a—(CH₂)₃— chain.

Preferred compounds of formula (IV) are notably those wherein

—R₁, R₂ represents a (C₂-C₆) alkyl group or form together a —(CH₂)₂— or—(CH₂)₄— chain; and/or

—X represents Cl, Br, I or CH₃SO₃—.

Most preferred compounds are notably the compounds of formula (IV)wherein:

X represents Cl, Br, I, CH₃SO₃— and/or R₁═R₂═C₂H₅ or R₁ and R₂ formtogether a —(CH₂)₂— chain.

The compounds of formula (IV) are particularly useful for preparing thecompounds of formula (I) and, as a result, are also advantageoussynthetic intermediates for the preparation of the compounds of formula(II).

Step iii)

The compounds of formula (I) thus prepared may be recovered from thereaction mixture by conventional means, for example the compounds may berecovered by distilling of the solvent from the reaction mixture or, ifnecessary, after distilling of the solvent from the reaction mixture,pouring the residue into water, followed by extraction with awater-immiscible organic solvent and distilling of the solvent from theextract. Additionally, the product can, if desired, be further purifiedby various well known techniques, such as recrystallization,reprecipitation or the various chromatography techniques, notably columnchromatography or preparative thin layer chromatography.

Methods for Preparing of the Compound of Formula (IV)

The compounds of formula (IV) according to the present invention may beprepared by the application or adaptation of known methods, by which aremeant methods used heretofore or described in the literature, forexample those described by R. C Larock in Comprehensive OrganicTransformations, VCH Publishers, 1989.

In another aspect, the invention is directed to a method for preparingthe compound of formula (IV).

The compound of formula (IV) may be prepared by the method comprisingthe steps of:

-   -   b1) reacting an aldehyde (VIl) with alcohols R₁OH and R₂OH or        HO—(CH₂)_(n)—OH, in the presence of an acid, wherein n, R₁ and        R₂ are as defined hereabove;

-   -   and optionally    -   c1) isolating the resulting compound (IV).

Preferably, the aldehyde (VII) is prepared by:

-   -   a1) oxidizing an alcohol of formula (VI) into the corresponding        aldehyde (VII);

wherein X represents an halogen atom, a (C₆-C₁₀) arylsulfonyloxy group,a (C₁-C₆) alkylsulfonyloxy group.

Step a1)

Conventional oxidizing agents may be used in accordance with standardpractice to convert primary alcohols into aldehydes. Precautions musthowever be taken so that the aldehyde is not further oxidized to thecarboxylic acid. For further information on that subject, reference maybe made to March's, Advanced Organic Chemistry, Michael B. Smith andJerry March.

Suitable oxidizing agents include DMSO, chromate salts such aspyridinium dichromate, Na₂Cr₂O₇, K₂Cr₂O₇, Cr₃ and NCS/tempo andtempo/NaOCl.

Different solvents may be used provided that they have no adverse effecton the reaction or on the reagent involved.

Examples of suitable solvents are notably halogenated hydrocarbons suchas dichloromethane, 1,2-dichloroethane, chloroform.

According to a preferred embodiment, the alcohol (VI) is oxidized bytempo/NaOCl in dichloromethane, in similar conditions than thosedisclosed in the publication J. Jurczak et al., Tetrahedron (1998), vol.54, p. 6051-6064.

Preferably, the group X of the compound (VI) represents a iodine atom.

Such compounds may be prepared from the corresponding compound offormula (IV), wherein X=Cl, Br or alkylsulfonyloxy, according toconventional methods,.

As an example, the compound of formula (VI), wherein X=Cl, may beconverted into X=I in the presence of NaI in DMF.

Step b1)

The acids which can be used in step b1) may be any conventional acidused for the protection of aldehydes under the form of a ketal.

Suitable acids include notably chlorhydric acid, sulfuric acid, nitricacid and phosphoric acid ; sulfonic acids such as methan sulfonic acid,ethane sulfonic acid, benzene sulfonic acid and paratoluene sulfonicacid. Of these, sulfonic acid and notably paratoluene sulfonic acid areparticularly preferred.

The molar ratio of acid is for example 0.001 to 0.5 equivalents, morepreferably 0.01 to 0.1 equivalents relative to the aldehyde VII.

The molar ratio of the alcohols R₁OH and R₂OH, or HO—(CH₂)_(n)—OH mayvary from 1.0 to 2.0 equivalents relative to the aldehyde VII, morepreferably from 1.0 to 1.1 inclusive.

In a preferred embodiment, the alcohol is HO—(CH₂)_(n)—OH, and morepreferably ethylene glycol.

As an example, this preferred embodiment of preparation is illustratedby the preparation of the compound (IVA) according to scheme 5.

The compounds of formula (IV) may also be prepared by the methodcomprising the steps of:

a2) reacting an aldehyde of formula (VIII) with a formaldehyde offormula (IX) in the presence of a base and an acid;

b2) converting the alcohol function of the compound (X) into an halogenatom or a (C₁-C₁₆) alkylsulfonyloxy group or a (C₆-C₁₀) arylsulfonyloxygroup; and optionally

c2) isolating the product obtained.

Step a2)

The preparation of compounds (X) in step a2) may be effected accordingto Tsuzuki et al., Tetrahedron Letters, Vol. 19, No. 11, p. 989-992(1978) and Matsuda et al., Tetrahedron (46(10), p. 3469-3488, (1990)).Analogues have been described by L. Paquette et al. (JACS 105(25), p.7352-7358, (1983 )) and by M. H. Seo et al. (J. of Korean Chem. Soc.,39(6), p. 489-491 (1995).

Step b2)

The reaction of step b2) may be effected according to conventionalmethods.

Preferably, the hydroxyl group of the compound (X) is converted into analkylsulfonyloxy or arylsulfonyloxy group.

This conversion may be effected according to conventional methods suchas reacting the compound (X) with an alkylsulfonyl or arylsulfonylhalide in the presence of a base.

Examples of suitable alkylsulfonyl or arylsulfonyl halides includenotably alkyl or arylsulfonyl chloride or bromide such as methylsulfonylchloride or p-toluenesulfonylchloride.

Examples of suitable bases include notably amines, preferably tertiaryamines such as triethylamine, diisopropylethylamine.

Examples of suitable solvents include aprotic solvents, notablyhalogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane.

This conversion of the hydroxyl group into an alkyl or arylsulfonyloxygroup can take place over a wide range of temperatures, notably between−10° C. and 100° C.

According to a preferred embodiment, the alkylsulfonyloxy orarylsulfonyloxy group is converted into an halogen atom.

Conventional methods may be used such as reacting the alkylsulfonyloxyor arylsulfonyloxy group with an alkali metal halide such as sodiumiodide, sodium bromide, lithium chloride.

Suitable solvents for this reaction are notably aprotic solvents, inparticular aprotic polar solvents such as N,N-dimethylformamide,N-dimethylsulfoxide acetonitrile.

As an example, this synthetic route is illustrated by the preparation ofcompound (IVA) in the following scheme 6.

Alternatively, the hydroxyl function of the compound (X) may beconverted directly into an halogen atom, according to conventionalmethods.

Conventional methods include notably reacting the alcohol (X) with theMe₃SiCl in DMSO, or PPh₃ in combination with CCl₄ or CBr₄.

For any further information regarding these methods, reference may bemade to M. B. Smith and J. March, in March's Advanced Organic Chemistry,5^(th) edition, Wiley Interscience.

In the reactions described hereabove, it may be necessary to protectreactive functional groups, for example amino or carboxy groups, wherethese are desired in the final product, to avoid their unwantedparticipation in the reactions. Conventional protecting groups may beused in accordance with standard practice, for example see T. W. Greenand P. G. M. Wuts in Protective Groups in Organic Chemistry, John Wileyand Sons, 1991; J. F. W. McOmie in Protective Groups in OrganicChemistry, Plenum Press, 1973.

The starting materials are commercially available or may be prepared bythe application or adaptation of known methods.

The compounds of the invention, their methods of preparation will appearmore clearly form the examination of the following examples, which arepresented as an illustration only and are not to be considered aslimiting the invention in its scope.

EXAMPLES Example 1 3-iodo-2,2-dimethyl-1-propandioxolane (Formula (IVA))

A) Preparation According to Scheme 5:

a) 3-iodo-2,2-dimethyl-propanol (Formula (VI): X═I (VIC))

80 g (0.53 mol) of dry Nal and 5 g (0.03 mol) of K₂CO₃ are added underargon to a solution of 50 g (0.4 mol) of3-chloro-2,2-dimethyl-1-propanol (formula VIA) in 75 ml of DMF. Themixture is stirred at reflux for 8 hours. The reaction mixture issubsequently brought to room temperature and diluted by addition of 500ml of water. The organic phase is extracted with 1050 ml of ethylacetate, washed with a saturated aqueous solution of Na₂SO₃, then with a250 ml of a saturated solution of sodium bicarbonate dried over 60 g ofanhydrous magnesium sulfate and evaporated to give crude compound offormula (VIC).

H¹RMN δ ppm: 0.97 (s,6H,CH₃); 2.48 (s, broad, OH); 3.17 (s, 2H, CH₂);3.37 (s,2H, CH₂).

¹³C RMN δ ppm: 20.3 (CH₂I); 23.7 (2C,CH₃); 35.5 (q, 1C); 69.7 (CH₂0)

b) 3-iodo-2,3-dimethyl-1-propanal (Formula (Vll)): X═I (VIIA))

100 ml of water are added under argon to a solution of 75.25 g (0.35mol) of the crude compound of formula VI in 300 ml of methylenechloride. Then 4.71 g (0.035 mol) of potassium bromide and 58.8 g ofsodium bicarbonate are added to the mixture. After cooling at −5° C.,0.546 g of TEMPO are added and the mixture is strongly stirred for 30mn. Then followed 275 ml of a solution of 10%-13% NaOCl (the reaction iscontrolled by TLC). The mixture is extracted with twice 250 ml ofmethylene chloride, washed with 400 ml of HCl 0.1N and then with 400 mlof a saturated solution of Na₂SO₃. The organic phase is dried over 5 gof sodium bicarbonate and evaporated. The organic oil is distillated at30° C. under 400 mbar to give 58 g of crude compound of formula (VII).

H¹RMN: δ ppm: 1.19 (s,6H,CH₃); 3.21 (s, 2H, CH₂I); 9.38 (s, 1H, CHO).

¹³C RMN δ ppm: 12.5 (CH₂I); 22.1 (2C,CH₃); 45.3 (q,1C); 201.9 (CHO).

c) 3-iodo-2,2-dimethyl-1-propandioxolane (formula (IVA))

58 g of the crude compound of formula VI are mixed with 61 ml ofethylene glycol, 0.778 g of paratoluenesulfonic acid in 155 ml oftoluene. The mixture is heated at reflux for 8 hours and 4-5 ml of waterare eliminated. The solution is washed with a saturated solution ofsodium bicarbonate and the organic phase is extracted with ethyl acetate(400 ml). After drying over sodium bicarbonate, the solvent isevaporated and the residue is distillated at 88-90° C. under 8-10 mbarto give 52 g of compound of formula (IVA). The overall yield for the 3steps is 50%

H¹RMN: δ ppm: 1.01 (s,6H,CH₃); 3.20 (s, 2H, CH₂I); 3.81-3.97 (m,4H,CH₂dioxolane); 4.65 (s,1H, anomeric).

¹³C RMN δ ppm: 18.2 (CH₂I); 22.4 (2C,CH₃); 37.4 (q); 65.4 (2C, CH₂O).

IR(film) cm⁻¹: 950; 1111.2; 1473.4; 1681.0; 2881.2; 2974.9 MS m/z=257[M+H].

B. Preparation According to Scheme 6:

a): 2-(2-hydroxy-1,1-dimethylethyl)-1,3-dioxolane (Formula(X))

To a stirred mixture of 100 g (1.4 mol) of isobutyraldehyde and 37%formaldehyde (150 g, 1.9 mole) was added 35 g (0.26 mol) of potassiumcarbonate by portions under cooling in an ice bath. The mixture iswarmed to room temperature and stirred over night. The organic layersare separated in two phases on standing and extracted with 400 ml oftoluene. The combined organic layers are dried over 20 g of anhydrousmagnesium sulfate and concentrated in vacuo to give 152 g of an oil.This crude oil is solubilized in 300 ml of toluene containing 205 ml ofethylene glycol and 3.5 g of paratoluenesulfonic acid. The mixture isheated at reflux under a Dean-Stark for 6-7 hours. After cooling at roomtemperature, the mixture is diluted with 300 ml of toluene, washed witha saturated solution of sodium bicarbonate, dried and concentrated togive 152 g of a crude compound of formula (X).

b) 2-(2-methansulfonyloxy-1,1-dimethylethyl)-1,3-dioxolane (Formula(XI))

The crude compounds of formula X (152 g, 1.03 mol) are solubilized in1.3 liter of methylene chloride containing 200 ml of Et₃N. The solutionis cooled to 0° C. and 100 ml of methanesulfonyl chloride are addedslowly. The mixture is then stirred for 30 minutes. 2.5 liters of waterare added and the organic layer is extracted with methylene chloride,washed with a saturated solution of sodium bicarbonate, dried oversodium bicarbonate and concentrated in vacuo. The residue is thendistillated at 110° C. under 0.1 mbar to give 150 g (yield: 66% ) ofcompound of formula (XI).

H¹RMN: δ ppm: 0.96 (s,6H,CH₃); 2.96 (s, 3H, CH₃O); 3.73-3.83 (m,4H, CH₂dioxolane);4.03 (s,2H, CH₂OMs); 4.63 (s,1H,anomeric).

IR(film) cm⁻¹: 842.2; 960; 1093; 1177 (SO₂); 1343 (SO₂); 1404.1; 1470;2974

MS m/z=225 [M+H]

c) 3-iodo-2,2-dimethyl-1-propandioxolane (Formula (IVA))

148 g (0.6 mol) of compound of formula (XI) are solubilized in 700 ml ofdimethylformamide containing 297 g (2 mol) of NaI. The mixture isstirred under reflux for 8 hours. 1 liter of a saturated solution ofNaCl are added. The organic layer is extracted with ethyl acetate (2×800ml), washed with a saturated solution of Na₂SO₃, and 200 ml of asaturated solution of sodium bicarbonate. After concentration anddistillation at 85-92° C. under 10 mbar, 142 g of compound of formula(IVA) are obtained.

Yield: 84%.

Example 22-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-methoxy-benzaldehyde(Formula (V): p=1; R=5-CH₃O; R1,R2=—CH₂—CH₂—: (VA))

A mixture of 70 g (0.27 mol) of compound of formula (IVA), 67.89 g (0.57mol) of potassium carbonate, 100 ml of 1-methyl-2-pyrrolidone, 67.89 g(0.57 mol), 25 g (0.16 mol) of 2-hydroxy-5-methoxy-benzaldehyde (formula(III)) is stirred at 132° C. for 3-4 hours. Then 25 g (0.16 mol) of2-hydroxy-5-methoxy-benzaldehyde solubilized in 25 ml of1-methyl-2-pyrrolidone are added and the mixture is stirred at 132° C.for 4 hours. 1 liter of a saturated solution of NaCl is then addedfollowed by 500 ml of water. The mixture is extracted with 1 liter ofdiisopropyl ether. The organic phase is washed with a solution of NaOH15%, dried over sodium bicarbonate and concentrated in vacuo to give 84g of crude compound (VA).

Yield of crude product: 100%.

Yield: 88% after purification with bisulfite.

Example 3E,Z-1-methoxy-2-(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy-)-5-methoxy-phenyl)-ethene(Formula (I): p=1; R=5-CH₃O; R1,R2=—CH₂—CH₂—: (IA))

1.6 g (14.28 mmol) of potassium terbutylate are added at −5° C. to asolution of 2.9 g (8.57 mmol) of [CH₃OCH₂P(Ph)₃]⁺Cl⁻ in 20 ml of THF.The mixture is stirred at 23° C. for 2 hours. Then 2 g (7.14 mmol) ofaldehyde (VA) are added. The mixture is stirred at room temperature for2 additional hours. 10 ml of a cold (ice) saturated solution of ammoniumchloride are added. The organic phase is extracted with 350 ml ofdiethyl ether. After drying over potassium carbonate and concentration,the residue is purified by chromatography

H¹RMN: δ ppm: 1.06 and 1.07 (s,6H,2CH₃); 3.67 (s, 2H, CH₂O); 3.72 and3.74 (s,3H,CH₃O);3.75 (s,3H,CH₃O); 3.85-3.94 (m,4H, CH₂ dioxolane), 4.85(s,1H, anomeric); 5.63 (d,0.3H, J=6HZ,CH═); 6.03 (d,0.7H, J=14HZ,CH═);6.15 (d,J=8HZ,CH═); 6.58-6.80 (m,2.7H,CH═); 7.12 (d,0.7H, J=12HZ,CH═);7.64 (d,0.3H,J=2HZ,CH═).

IR(film)cm⁻¹: 1049; 1111; 1222; 1464; 1497; 1641;2966 MS m/z=309 [M+H]

Yield: 94%.

Example 4 3,3-dimethyl-5-formyl-7-methoxy-2,3-dihydrobenzoxepine(Formula (II): p=1; R=7-CH₃O; (IIA))

To a solution of 180 g (0.58mol) (IA) in 4 liters of dimethylformamideis added 1.7 liter of 28% sulphuric acid. The temperature goes up to 70°C. After cooling to 35-40° C., the mixture is then heated at 75° C. for16 hours. The mixture is cooled to room temperature. 3 liters of waterare added and the organic phase is extracted with ethyl acetate. Afterwashing with a saturated solution of sodium bicarbonate (pH should bebetween 6 and 8) and drying over magnesium sulphate, the solvent isevaporated in vacuo and the residue purified by chromatography. Afterpurification, the compound obtained is identical to the compoundobtained in example 16 i) of [EP 1140893 B1, yield: 96%].

Yield: 100%.

Example 5 3-bromo-2,2-dimethyl-1-propandioxolane(Formula (IV): X=Br, R₁and R₂ are —CH₂—CH₂-(IVB))

To a solution of 4 g (20 mmol) of 3-bromo-2,2-dimethyl-propanol (formula(VI): X=Br (VIA)), 1 g of molecular sieves (4OA) in 50 mldichloromethane cooled to 0° C., are added 6 g (30 mmol) of pyridiniumchlorochromate (PCC) on Celite (50/50). After 30 minutes, the solvent isevaporated and the crude residue (aldehyde of formula (VII)) isextracted with diethyl ether. After concentration at 17° C. under 75mbar, the residue is treated according to example 1 A) c) anddistillated at 68° C. under 2.5 mbar to give compound (IVB).

H¹RMN: δ ppm: 0.99 (s,6H,2CH₃); 3.35 (s, 2H, CH₂Br); 3.78-3.94(m,4H,CH₂O); 4.69(s,1H, anomeric)

¹³C RMN δ ppm: 21.3 (2C,CH₃); 38.5 (q); 65.8 (2C, CH₂O); 107.8(anomeric).

IR(film) cm⁻¹: 1001; 1474; 2883; 2970.

[Yield: N]

Example 6 1-chloro-2,2-dimethyl-3,3-diethoxy-propane (Formula (IV):X=Cl, R₁=R₂=CH₃CH₂— (IVC))

A solution of 6.76 ml (77.5 mmol) de (COCl)₂ in 220 ml of drydichloromethane is cooled to −40° C. Then 153.8 ml (10.9 mmol) ofdimethylsulfoxide are added slowly. 5 minutes later, a solution of 7.5 gof 1-chloro-2,2-dimethyl-propanol (formula (VIC): X=Cl) in 61 ml ofdichloro-methane is added. The mixture is stirred for 15 minutesfollowed by the addition of 36 ml (264.3mmol) de Et₃N. 30 ml ofdichloromethane are added and the mixture is warmed to room temperature.The organic phase is washed with water (3×150 ml), dried over sodiumsulfate, concentrated in vacuo (17° C./75 mbar). The oil obtained issolubilized in ethanol and the solution is heated under reflux with acatalytic amount of PTSA for 120 minutes, concentrated in vacuo (19°C./32 mbar). After distillation at 62-65° C. under 10 mbar, 8 g ofcompound (IVC) are obtained (yield: 68%).

H¹RMN δ ppm: 0.96 (s,6H, 2CH₃); 1.25 (t, 6H,J=8HZ; OCH₂ CH₃ );3.44(s,2H,CH₂Cl); 3.48-3.57 (m,2H,CH₂O); 3.75-3.88 (m,2H, CH₂O); 4.25(s,1H,anomeric)

¹³C RMN δ ppm: 15.4 (2C,CH₃); 20.4 (2C, OCH₂ CH₃ ); 41.4 (q);53.1(CH₂Cl);65.8 ((2C, OCH₂CH ³ ); 107.7 (anomeric).

IR(film) cm⁻¹: 656; 1063; 1249; 1381;1474;

MS m:z=159

Example 7 1-bromo-2,2-dimethyl-3,3-diethoxy-propane (Formula (IV): X═Br,R₁=R₂=CH₃CH₂— (IVD))

Prepared according to example 6; boiling point: 74-78° C. under 10 mbar

H¹RMN: δ ppm: 0.92 (s,6H,2CH₃); 1.12 (t,6H,J=6HZ; OCH₂ CH₃ );3.28(s,2H,CH₂Cl); 3.42-3.53 (m,2H,CH₂O); 3.65-3.80 (m,2H, CH₂O); 4.17(s,1H,anomeric)

¹³C RMN δ ppm: 15.2 (2C,CH₃); 21.0 (2C, OCH₂ CH₃ ); 40.3 (q);43.4(CH₂Br); 66.1 ((2C, OCH₂CH ³ ); 107.9 (anomeric).

IR(film) cm⁻¹: 656; 1063; 1249; 1381;1474;

MS m:z=159

Yield: 79%.

Example 8 1-methanesulfonyloxy-2,2-dimethyl-3,3-diethoxy-propane(Formula (IV): X=CH₃SO₃, R₁=R₂=CH₃CH₂— (IVE))

A solution of 0.175 mol of 2,2-dimethyl-propanediol-1,3 in methylenechloride is cooled to −5° C.Then one equivalent of pyridine is addedunder inert atmosphere, followed 30 minutes later by one equivalent ofmethanesulfonyl chloride. The mixture is warmed to room temperature andstirred for one week. The solution is washed with 250 ml of HCl 0.1N,dried over magnesium sulfate, evaporated in vacuo to give 30 g of crude2,2-dimethyl-1-methanesulfonyloxy-propanol (yield: 68%).

The crude alcohol is treated according to example 5 to give afterdistillation at 98° C. under 0.1 mbar the compound of formula (IVE).

H¹RMN: δ ppm: 0.89 (s,6H,2CH₃); 1.12 (t, 6H,J=6HZ; OCH₂ CH₃ );2.90(s,3H,CH₃ SO₃); 3.36-3.51 (m,2H,CH₂O); 3.65 3.80(m,2H,CH₂O);3.95(s,2H,CH ³ SO₃CH₂ ); 4.12(s,1H,anomeric)

¹³C RMN δ ppm: 15.2 (2C,CH₃); 19.2 (2C, OCH₂ CH₃ ); 36.5 (CH ³ SO₃);40.1(q); 66.0 ((2C, OCH₂CH ³ ); 75.7 (CH ³ SO₃ CH₂); 107.7 (anomeric).

MS m:z=181

Example 9 2-(2,2-dimethyl-3,3-diethoxy-propoxy-)-5-methoxy-benzaldehyde(Formula (V) : p=1; R=5-CH₃O; R1,R2=CH₃CH₂O—: (VB))

Prepared according to example 2 from 2-hydroxy-5-methoxy-benzaldehyde(formula (III)) and compounds of examples 6 or 7 or 8 to give compoundof formula (VB).

H¹RMN: δ ppm: 1.05 (s,6H,2CH₃); 1.17 (t, 6H,J=6HZ; OCH₂ CH₃ );3.47(m,2H,CH ² O); 3.76-4.88(m,7H); 4.33 (s,1H, anomeric); 6.93 (d,1H,J=10HZ,CH aromatic); 80(m,2H,CH₂O); 3.95(s,2H,CH ³ SO₃CH₂ ); 4.12(s,1H,anomeric); 7.10 (dd,1H,J=4HZ,10HZ,CH aromatic); 7.29 (d,1H,J=4HZ,CH aromatic); 10.50 (s,1H,CHO)

¹³C RMN δ ppm: 15.4 (2C,CH₃); 19.9 (2C, OCH₂ CH₃ ); 40.8 (q); 55.8((1C,OCH ³ ); 66.3 (2C,CH ² O); 75.07 (CH ² O);108.0 (anomeric); 110.0(CH aromatic); 114.4 (CH aromatic); 123.7 (CH aromatic); 124.7 (q, CHaromatic); 153.5 (q, CH aromatic); 156.6 (q, CH aromatic); 189.4 (CHO).

IR(film)cm⁻¹: 1115; 1219; 1497; 1681;1686;2878;2975.

Example 10E,Z-1-methoxy-2-((2,2-methyl-3,3-diethoxy)propoxy-)-5-methoxy-phenyl)-ethene(formula (I): p=1; R=5-CH₃O; R1,R2=CH₃CH₂O: (IB))

Prepared according to example 3 from compound of example to givecompound of formula (IB)

H¹RMN: δ ppm: 0.98 and 0.99 (s,6H,2CH₃); 1.07-1.15 (t, 6H,J=6HZ, OCH₂CH₃ ); 3.43 (m,2H,CH₂O);3.62-3.78 (m,10H,); 4.33 (s,1H, anomeric);5.58(d,0.6H, J=8HZ,CH=); 5.97 (d, 0.4H, J=12HZ, CH=); 6.10 (d,0.6H,J=8HZ,CH=); 6.53-6.74 (m,2.4H); 7.05 (d,0.4H,CH=); 7.59(m,0.0.6H).

1. A compound of general formula (I):

wherein R is, in each case independently, (C₁-C₁₈)alkoxy; p represents0, 1, 2, 3 or 4; R₁ and R₂ are each independently (C₁-C₁₈)alkyl ortogether form -(CH₂)_(n)-; and n represents 2, 3 or
 4. 2. A compoundaccording to claim 1,wherein R is methoxy, ethoxy, isopropyloxy, butoxy,and hexyloxy.
 3. A compound according to claim 1, wherein R representsmethoxy.
 4. A compound according to claim 1, wherein R represents7-methoxy.
 5. A compound according to claim 1, wherein p is
 1. 6. Acompound according to claim 1, wherein R₁ and R₂ represent independentlya (C₁-C₄) alkyl group.
 7. A compound according to claim 1, wherein R₁and R₂ represent ethyl or form together a -CH₂-CH₂ - group.
 8. Acompound according to claim 1, wherein said compound is selected fromFormulas IA and IB:


9. A method for preparing a compound of formula (I) according to claim1, comprising: ii) reacting an aldehyde (V) with a phosphorus ylidprepared from the reaction of a phosphonate (XIIa) or phosphonium salt(XIIb) with a base,

wherein T₁ and T₂ represent independently (C₁-C₅)alkyl, and T₃, T₄, T₅represent independently (C₁-C₅) alkyl or (C₆-C₁₀)aryl, and iii)optionally isolating the obtained compound of formula (I).
 10. A methodaccording to claim 9, wherein the aldehyde (V) is prepared by: i)reacting a compound of formula (III) with a compound of formula (IV) inthe presence of a base

wherein R, R₁, R₂ and p are as defined in formula (I),and X representshalogen, (C₁-C₆) alkylsulfonyloxy, (C₆-C₁₀) aryl-sulfonyloxy.
 11. Amethod according to claim 9, wherein the phosphorus ylid of ii) isprepared by reacting a base on a phosphonium salt.
 12. A methodaccording to claim 9, wherein the base in ii) is an alkali metalhydride, an alkali metal carbonate, a (C₁-C₁₀) alkyllithium, or analkali metal alkoxide.
 13. A method according to claim 9, wherein ii) isperformed in an aprotic solvent selected from aromatic hydrocarbons,ethers, polar aprotic solvents, and mixtures thereof.
 14. A methodaccording to claim 9, wherein the phosphorus ylid is prepared byreacting an alkali metal alkoxide with a phosphonium salt (XIIb) at atemperature of between −10° and 100° C.
 15. A method according to claim10, wherein the base in i) is an alkali metal carbonate, alkali metalhydride, (C₁-C₁₀) alkylithium, or an alkali metal alkoxide.
 16. A methodaccording to claim 10, wherein i) is performed in an aprotic solventselected from polar aprotic solvents, aromatic hydrocarbons or mixturesthereof.
 17. A method according to claim 10, wherein the compound offormula (IV) is prepared by: b1) reacting an aldehyde (VII) withalcohols R₁OH and R₂OH or HO—(CH₂)_(n)—OH, in the presence of an acid,wherein n, R₁ and R₂ are as defined in formula (I); and optionally

c1) isolating the resulting compound (IV).
 18. A method according toclaim 17, wherein the aldehyde of formula (VII) is prepared by: a1)oxidizing the alcohol of formula (VI) into the corresponding aldehyde offormula (VII)

wherein X represents halogen, (C₁-C₆) alkylsulfonyloxy,(C₆-C₁₀)arylsulfonyloxy.
 19. A method according to claim 18, wherein thealcohol of formula (VI) is oxidized by2,2,6,6,-tetramethylpiperidinyloxy in combination with NaOCl.
 20. Amethod according to claim 10, wherein the compound of formula (IV) isprepared by: a2) reacting an aldehyde formula (VIII) with theformaldehyde (IX) in the presence of a base and an acid to obtain ahydroxyl compound of formula(X);

b2) converting the hydroxyl function of the compound (X) into an halogenatom, a (C₁-C₆) alkylsulfonyloxy group, or an (C₆-C₁₀) arylsulfonyloxygroup; to obtain a compound of formula (IV); and optionally c2)isolating the compound of formula (IV) obtained.
 21. A compoundaccording to claim 1, wherein R₁ and R₂ are each independently methyl,ethyl or isopropyl group.
 22. A compound according to claim 1, whereinR₁ and R₂ together form together -(CH₂)_(n)- in which n is 2 or
 3. 23. Acompound according to claim 8, wherein said compound is of Formula IA.24. A compound according to claim 8, wherein said compound is of FormulaIB.
 25. A compound according to claim 1, wherein said compound is: E,Z-1-methoxy-2(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy)-3-methoxy-phenyl)-ethene;or E,Z- 1 -methoxy-2(2-(2-methyl-2-(1,3-dioxolan-2-yl)propoxy)-4,5-dimethoxy-phenyl)-ethene.
 26. A compoundaccording to claim 1, wherein said compound is:E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-3-methoxy-phenyl)-ethene;E,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-4,5-dimethoxy-phenyl)-ethene;orE,Z-1-methoxy-2-(2-(2,2-dimethyl-3,3-diethoxy)propoxy-)-5-methoxy-phenyl)-ethene.